Cocaine is commonly believed to induce its psychostimulant and behavioral effects through inhibition of monoamine transporters, dopamine transporters (DAT) in particular. Brain cocaine levels in self- administering animals and human addicts can be around 5 ?M and may affect neuronal targets besides monoamine transporters. Studies also show that cocaine inhibits cloned neuronal nicotinic acetylcholine receptors (nAChRs). More important, recent reports indicate that nAChR activity regulates dopamine (DA) release and affects cocaine's behavioral effects, suggesting potential interactions between cocaine and nAChRs in the DA system. Our preliminary data support our hypothesis that, in addition to DAT inhibition, cocaine may inhibit the presynaptic nAChRs on DA terminals in the striatum and reduce initial DA release probability. Consequently, cocaine may reduce single pulse-evoked tonic DA release and favor the reward-related phasic DA release. This novel cocaine mechanism may thus increase the phasic to tonic DA ratio, potentially enhancing the saliency and motivational value of cocaine-related reward signals. Our preliminary results indicate that at low levels (<2 ?M), cocaine primarily enhances the DA signal through the well known uptake inhibition mechanism. At higher levels attained in cocaine abusers, novel mechanisms come into play. Of particular importance, at 2-10 ?M attained in abusers, cocaine may inhibit presynaptic nAChRs and decrease the initial DA release probability, and enhance the reward-related phasic to tonic DA signal ratio. Overall, these proposed projects will delineate novel, presynaptic nAChR-mediated cocaine mechanisms that favor reward-related phasic DA release. These novel, non-transporter cocaine mechanisms, in concert with monoamine transporter-dependent mechanisms, are likely to contribute to cocaine's addictive properties. These results will also provide guidance to our future projects using in vivo animal models, and contribute to our long term goals to elucidate the neuronal mechanisms of cocaine and nicotine abuse, potentially leading to more effective prevention and treatment strategies for these problems.